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LaMichael James will begin his second season where his rookie year began: on the sideline.

The 49ers running back sustained a sprained medial collateral ligament in his left knee during a 41-6 win over the Chargers on Thursday night in the preseason finale, a league source said. James has a Grade 2 sprain and is expected be sidelined three to four weeks, the Sacramento Bee reported. If that timeline is accurate, James will miss a minimum of two regular-season games.

Without James, Frank Gore and Kendall Hunter will split carries in the backfield, with Anthony Dixon possibly being in line for some action. It’s likely that wide receiver Kyle Williams will return punts with James sidelined. Williams, who was listed as the team’s backup punt returner on the team’s unofficial preseason depth chart, averaged 13.0 yards on four returns when Ted Ginn missed the first three games of 2012.

Williams did not play in the preseason, but has been practicing without restrictions. The 49ers took a cautious approach this summer with Williams returning from a torn ACL he sustained in late November.

If the 49ers want to ease Williams into the regular season, another punt-return candidate is Perrish Cox, who is expected to make the team as the No. 5 cornerback. At Oklahoma State, Cox averaged 11.6 yards on 60 returns and scored two touchdowns. He appeared very comfortable in that role in the preseason and averaged 12.0 yards on three returns.

Williams, rookie wide receiver Quinton Patton and Cox are candidates to return kickoffs, a role in which James excelled last year, averaging 29.8 yards on 14 returns.

James, who was inactive for the first 12 games of his rookie season, had 55 yards on 24 carries (2.3 yards per carry) during the preseason. Last year, the 2012 second-round pick had 190 yards on 38 carries (5.0) and a 15-yard touchdown run in the NFC Championship Game.